New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment John Wells, MD MS Shyam Paryani, MD MS MHA First Radiation and

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1 New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment John Wells, MD MS Shyam Paryani, MD MS MHA First Radiation and

2 We have no financially related disclosures However, we do have two other disclosures to make.

3 We are involved in a protocol testing the utility of biomarkers of breath and blood in the detection of lung cancer, and

4 We have Super Powers & X-ray Vision!!

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6 Especially for Lung Cancer

7 Regarding the Status Quo Therapeutic Nihilism

8 Comparative Mortality

9 Your Own Bad Karma Will Get You Quicker Than Others!

10 Mortality is high because almost 60% of people have distant disease at presentation

11 Mortality would be different if disease presented early rather than late. Gainesville, Florida Stage IA (T1a<2cm/T1b<3cm, N=0, M=0)

12 How small does small need to be to cure 90%(+)? T1a< 1 cm T1a< 2cm T1b < 3cm T2a< 5cm T2b< 7cm 80-90% 75% 70% 60% 50% how do you find these now? T3> 7cm 35%

13 Such is the need for Frontier technologies to chip away at the status quo

14 New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment Parts I III relates to small and curable Part IV relates to large and incurable

15 John, do you think we it Yes, because framesreview the should thediscussion NLST trial first?

16 Solitary Pulmonary Nodules < 3cm 150,000 on CXR. 450,000 on CT 88% of SPNs are less than 1cm. Pulmonologists use Fleischner society guidelines and clinical suspicion to determine who receives a biopsy

17 The NLST Trial Studied 54,000 people at high risk for lung cancer between 2002 and 2004 with either a Chest X-ray or a Chest CT. Criteria: Age: 55 thru 74. Smoking: greater than 30 pack years. Interval since cessation: Less than 15 years from the last cigarette. Cancer: No known cancer. Three screenings were done at one year intervals. For each interval CT revealed more lesions than CXR by a

18 NLST (N=53,000); Annual LDCT x 3 vs. CXR x 3 Lung Cancer Case Survival The Big Deal LDCT 20% Chest X-Ray For the first time a way to reduce to reduce LC mortality via screening was shown Table d

19 The NLST Trial Current Status of Lung Cancer Screening. Seminars in Thoracic and Cardiovascular Surgery. Vol It pays to find lung cancer early

20 There was a problem 96% of the positive LDCTs were false positive.

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22 Regarding Specificity Improve LDCT specificity through noninvasive testing designed to: Reduce the rate of unnecessary investigation. Increase accuracy Minimize Treatment Delay A Tall Order

23 New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment It s all about finding things while they are small Part I

24 Today Tomorrow

25 Lung Cancer: Detection

26 Lung Cancer: Detection: Autoantibodies Early CDT-Lung test An aid to the detection of lung cancer Tests for concentrations of 7 autoantibodies Commercially available Gradually being acccepted Part I: A

27 Lung Cancer: Detection: Antibodies Part I:A OncImmune s Seven Antibodies p53 NY-ESO-1 CAGE GBU4-5 SOX-2 HuD MAGE A4 Observations For every 32 patients with a positive 7 antigen EarlyCDTlung, 5 are diagnosed with lung cancer in 6 months. For every 179

28 The good news: Tumors may be detected by autoantibodies at two or more millimeters. The bad news: Tumors that can not be detected by imaging methodologies may make create diagnostic havoc.

29 Lung Cancer: Detection: Proteins Part I:B We are all familiar with Carcinoembryonic Antigen(CEA), a fetal cell surface protein that is found in certain malignancies including AC Lung There are other proteins that are associated with Lung Cancer as well.

30 Type Lung Cancer: Detection: Proteins Part I:B SCC >2ng/ml Pro-GRP >50pg/ml NSE >25ng/ml CYFRA 21-1 >3.3 ng/ml CEA >5 ng/ml CA 15.3 >35U/ml SQ 41% 25% 13% 70% 42% 26% AC 8% 9% 8% 54% 70% 47% LC 11% 21% 16% 53% 16% 14% NOS 11% 11% 6% 53% 47% 52% CEA Carcinoembryonic Antigen CA 15.3 Carcinoma Antigen 15.3 CYFRA A Cytokeratin 19 fragment NSE: Neuron-Specific Enolase Pro-GRP: Pro-gastrin Releasing Peptide SCC: Squamous Cell Carcinoma Antigen The Frontier question is whether or not statistical analysis of a panel of such tests will be more predictive of lung cancer than any one test.

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32 Lung Cancer: Detection: Breath Potentially Paradigm changing technology Israeli Institute of Technology Thorac Oncol. 2012;7: Nanomedicine. In Press Part I:C

33 Lung Cancer: Detection: Breath Part 1:C Thousands of Volatile Organic Compounds are exhaled with each breath. Investigators in Israel are working on nanoparticle based chips to identify VOCs associated with lung cancer, cancer histology, and Genetic mutations Work is under way to validate these observations and determine their utility in assisting the Pulmonologist in their decision to act on SPNs and Medical Oncologists in their

34 Discrimination between Benign* and Malignant Nodules Part I:C Malignant/ Benign SCLC/NSCLC Sensitivity Specificity Accuracy PPV NPV Peled N et al. Journal Thoracic Oncology, 2012

35 Discrimination between Histology Part 1:C (a) (b)

36 In-Vitro Classification of Lung Cancer Genetic Mutations Part 1:C

37 In-Vitro Classification of Lung Cancer Genetic Mutations EGFR = Epidermal Growth Factor Receptor; KRAS = v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog; ALK = Anaplastic Lymphoma receptor tyrosine Kinase

38 This IS Frontier Medicine Signatures have been obtained from other cancers and diseases including Colon Ovary Pancreas H Pylori TB Don t be surprised

39 New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment Part II

40 Lung Cancer: Diagnosis Part II

41 Lung Cancer: Diagnosis: ENB Part II:A S u p e r D i m e n si o n Virtual 3D bronchial tree extends deep into the lungs reaching 17+ airway generations. Multiple guidance and navigation views enhance lung lesion and vessel visualization. Diagnostic yield of %1,2,3 for lesions and 100% for lymph nodes4

42 Lung Cancer: Diagnosis: ENB Benefits Part II:A For Pulmonologists For Thoracic Surgeons Allows access throughout the lung. Through pleural based blue dye marking or placement of fiducials, small lesions can be localized for excision. For SBRT Radiation Oncologists Fiducials facilitate precise localization/tracking

43 Lung Cancer: Diagnosis: EBUS Part II:B

44 Lung Cancer: Diagnosis: EBUS Part II:B Diagnosis of hilar/ mediastinal lymphadenopathy of unknown etiology Evaluation of hilar/ mediastinal LN in Lung cancer Evaluation of LN in metastatic lung tumors Diagnosis of solitary pulmonary nodules Evaluation of endobronchial tumors

45 Lung Cancer: Diagnosis: EBUS Benefits Part II:B EBUS is an alternative to Cervical Mediastinoscopy in the staging of Lung Cancer. When coupled with ENB, it is possible to diagnose and stage in one setting. Many surgeons take exception to staging via EBUS rather than Cervical Mediastinocopy.

46 EBUS can replace mediastinoscopy for accurate staging of the mediastinum in potentially resectable lung cancer, Interventional Pulmonologist Thoracic Surgeon

47 A negative EBUS-FNA should be followed by a Transcervical Mediastinoscopy Interventional Pulmonologist Thoracic Surgeon

48 New Frontiers in Lung Cancer Detection, Diagnosis, and Treatment Part III

49 Lung Cancer: Treatment Part III

50 Lung Cancer: Treatment: Surgical Part III:A/B VATs Robotics Both VATs and Robotic VATs minimize the morbidity of Thoracotomy. Robotic VATs represents the next Frontier in the surgical management of lung

51 Regarding Robotic-Assisted Lobectomy Facilitates both precise isolation of vascular structures and meticulous dissections. MiniIwaReduces Iatrogenic trauma limiting air leaks (6.3%) Limiting blood loss Reduces post-op bleeding and transfusion rate ( 1.6% %) McKenna, 07- transfusion rate 4.1% Limited manipulation of lung and tumor mass (No touch technique) Reduces likelihood of tumor translocation May attribute to low rates of SVT (2.9%) VATS lobectomy: Rate SVT (McKenna, %, Duke University, %)

52 Value of Robotic-Assisted Lobectomy Over Conventional VATS Lobectomy Models conventional surgical techniques Improved accuracy of dissection Allows precise isolation of vascular structure Meticulous dissection Reduces Iatrogenic trauma limiting air leaks (6.3%) Limiting blood loss Reduces post-op bleeding and transfusion rate ( 1.6% %) McKenna, 07- transfusion rate 4.1% Limited manipulation of lung and tumor mass (No touch technique) Reduces likelihood of tumor translocation May attribute to low rates of SVT (2.9%)

53 Value of RVATS Over Conventional VATS Lobectomy No need for access incision Performed through 4 ports often positioned along a single rib space No need for extension of thoracic incisions to remove lobe Reduced pain and neuralgia Reduces morbidity and mortality Wider utilization Locally advanced disease Large tumor size Reduced port site recurrences

54 Value of RVATS Over Conventional VATS Lobectomy No need for access incision Performed through 4 ports often positioned along a single rib space No need for extension of thoracic incisions to remove lobe Reduced pain and neuralgia Reduces morbidity and mortality Wider utilization Locally advanced disease Large tumor size Reduced port site recurrences

55 Lung Cancer: Treatment: SBRT Part III:B Novalis Cyberknife Stereotactic Body Radiation Therapy High Dose, Short Course, Precisely delivered XRT 6,000/30 vs 6,000/3 BED of 72 vs BED of Both require sophisticated treatment planning equipment.

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57 Ref Radiosurgery: 2012 Part III:C n Median FU (mo) LC % Comment PMID 2012 Lung Cancer / Japan Bx proven vs No bx (clinical dx). Argues for no bx J Thoracic Oncol Of 16 pts alive and NED at >5 years, 4 developed recurrence. ¾ of which had a component of 76, 101, 108, 109mo p SBRT IJROBP / VU yr Pts with severe COPD IJROBP / PMH yr 4yr Median size 2.4cm. CSS 92%, 1,4 years Lancet yr 5yr Median TTR = 14.9mo. 2,5 year rates: 7.8,12.7 regional, 14.7,19.9 distant J Thorac Oncol / Beaumont yr 63% IA, 33% IB, 2% IIA, recurrent 1%. Median tumor 2.6cm. Regional Control 89%, DM 20%. Median dose 54 Gy / 3fx. Stage, tumor size and dose predicted local relapse J Thorac Oncol / Mass General yr 42-50Gy in 3-5 fx. Proton SBRT

58 Radiosurgery: 2012 Part III:C Ref n Median FU (mo) LC % Comment PMID 2012 Lung Cancer / Japan Bx proven vs No bx (clinical dx). Argues for no bx J Thoracic Oncol Of 16 pts alive and NED at >5 years, 4 developed recurrence. ¾ of which had a component of 76, 101, 108, 109mo p SBRT IJROBP / VU yr Pts with severe COPD IJROBP / PMH yr 4yr Median size 2.4cm. CSS 92%, 1,4 years Lancet yr 5yr Median TTR = 14.9mo. 2,5 year rates: 7.8,12.7 regional, 14.7,19.9 distant J Thorac Oncol / Beaumont yr 63% IA, 33% IB, 2% IIA, recurrent 1%. Median tumor 2.6cm. Regional Control 89%, DM 20%. Median dose 54 Gy / 3fx. Stage, tumor size and dose predicted local relapse J Thorac Oncol / Mass General yr 42-50Gy in 3-5 fx. Proton SBRT Seven Articles

59 Radiosurgery: 2012 Part III:C Ref n Median FU (mo) LC % Comment PMID 2012 Lung Cancer / Japan Bx proven vs No bx (clinical dx). Argues for no bx J Thoracic Oncol Of 16 pts alive and NED at >5 years, 4 developed recurrence. ¾ of which had a component of 76, 101, 108, 109mo p SBRT IJROBP / VU yr Pts with severe COPD IJROBP / PMH yr 4yr Median size 2.4cm. CSS 92%, 1,4 years Lancet yr 5yr Median TTR = 14.9mo. 2,5 year rates: 7.8,12.7 regional, 14.7,19.9 distant J Thorac Oncol / Beaumont yr 63% IA, 33% IB, 2% IIA, recurrent 1%. Median tumor 2.6cm. Regional Control 89%, DM 20%. Median dose 54 Gy / 3fx. Stage, tumor size and dose predicted local relapse J Thorac Oncol / Mass General yr 42-50Gy in 3-5 fx. Proton SBRT Seven Articles 24.2 Mo.

60 Radiosurgery: 2012 Part III:C Ref n Median FU (mo) LC % Comment PMID 2012 Lung Cancer / Japan Bx proven vs No bx (clinical dx). Argues for no bx J Thoracic Oncol Of 16 pts alive and NED at >5 years, 4 developed recurrence. ¾ of which had a component of 76, 101, 108, 109mo p SBRT IJROBP / VU yr Pts with severe COPD IJROBP / PMH yr 4yr Median size 2.4cm. CSS 92%, 1,4 years Lancet yr 5yr Median TTR = 14.9mo. 2,5 year rates: 7.8,12.7 regional, 14.7,19.9 distant J Thorac Oncol / Beaumont yr 63% IA, 33% IB, 2% IIA, recurrent 1%. Median tumor 2.6cm. Regional Control 89%, DM 20%. Median dose 54 Gy / 3fx. Stage, tumor size and dose predicted local relapse J Thorac Oncol / Mass General yr 42-50Gy in 3-5 fx. Proton SBRT Seven Articles 24.2 Mo. 90% LC

61 SBRT has clearly established a role for itself in the management of early stage medically inoperable patients High Dose Short Course precise and painless SBRT has few Complications. It is unlikely that the broom of establishment criticism can stop the SBRT tide

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63 Lung Cancer: Treatment: SBRT BMC experience: Local Control Based on analysis of 90 cases we have treated (with 82/90 being treated for cure) with a median follow up of 18 months T1a: 100% (0 failures/20) T1b: 95% (2 failures/40) T2: 85% ( 4 failures/ ) T3: 50% (1 failure/2) Over all local control at 18 months is 91% Further follow is needed.

64 LOCAL CONTROL: CURATIVE PTs BY T STAGE KM LF Survival probability (%) adj_t 2 3 1a 1b Number at risk Group: 2 31 Group: 3 3 Group: 1a 16 Group: 1b Time Courtesy of Michael Olson, MD PhD

65 LOCAL CONTROL:KMCURATIVE INTENT LF Survival probability (%) Number at risk Time Courtesy of Michael Olson, MD PhD

66 LOCAL CONTROL: CURATIVE PTs BY T STAGE KM LF Survival probability (%) adj_t 2 3 1a 1b Number at risk Group: 2 31 Group: 3 3 Group: 1a 16 Group: 1b Time Courtesy of Michael Olson, MD PhD

67 Part IV The best hope we have to help more people now

68 Personalized Medicine When Oncologists speak of Personalized medicine they are speaking of a therapeutic approach where the results of standardized biomarker testing to identify disease specific genes or gene profiles associated with cancer growth are used to select drugs for treatment This is targeted therapy.

69 Biomarkers in Advanced Lung Cancer Over the last decade, a growing number of biomarkers (proteins) have been identified in NSCLC Epidermal growth factor receptor (EGFR)* Anaplastic lymphoma kinase (ALK)* v-ki-ras2 Kirsten rat sarcoma (KRAS) Human epidermal growth factor receptor-2 (HER2)

70 Biomarkers in Advanced Lung Cancer

71 EGFR Expression

72 EGFR Inhibition in Lung Cancer (EGFR:Epidermal Growth Factor Receptor) 20% - 30% of lung cancers have EGFR mutations Often in female never-smokers (80%) (70%) Responses last for approximately three months

73 ALK Inhibition (ALK: Anaplastic Lymphoma Kinase) Only 2% - 7% of patients will have this mutation. Tends to be found in younger never-to-light smokers 70% of such patients respond to Crizotinib (XALKORI) with disease stabilization up to six months Interestingly, patients with this mutation do not

74 It s easy to see why technology has tumor characterization from histology-based to targeting oncogenic drivers 1999 Histology-driven selection 2010 Targeting oncogenic drivers* Evolution of NSCLC treatment Non-squamous Squamous Adenocarcinoma EGFR Mu Squamous-cell carcinoma Large cell carcinoma KRAS PIK3CA EGFR ALK BRAF MET HER2 Unknown EGFR ALK+ Mu *Incidence of mutations in adenocarcinoma provided as an example EGFR WT KRAS Mu Squamous 2008 Other nonsquamous Squamous Today WT Current Standard of NSCLC Care 74

75 Treatment selection is moving from histology-based to targeting oncogenic drivers 1999 Histology-driven selection 2010 Targeting oncogenic drivers* Evolution of NSCLC treatment Non-squamous Squamous Adenocarcinoma EGFR Mu Squamous-cell carcinoma Large cell carcinoma KRAS PIK3CA EGFR ALK BRAF MET HER2 Unknown EGFR ALK+ Mu *Incidence of mutations in adenocarcinoma provided as an example EGFR WT KRAS Mu Squamous 2008 Other nonsquamous Squamous Today WT Current Standard of NSCLC Care 75

76 Treatment selection is moving from histology-based to targeting oncogenic drivers 1999 Histology-driven selection 2010 Targeting oncogenic drivers* Evolution of NSCLC treatment Non-squamous Squamous Adenocarcinoma EGFR Mu Squamous-cell carcinoma Large cell carcinoma KRAS PIK3CA EGFR ALK BRAF MET HER2 Unknown EGFR ALK+ Mu *Incidence of mutations in adenocarcinoma provided as an example EGFR WT KRAS Mu Squamous 2008 Other nonsquamous Squamous Today WT Current Standard of NSCLC Care 76

77 Lung Cancer: Treatment: Personalized Personalized medicine is not curative. It can certainly help the Oncologist target the tumor with the most effective treatment for the fortunate 10%. It is very expensive, however, and monitoring is often difficult. One can only hope that non invasive biomarker technologies of blood and breath will someday be used to streamline and

78 In-Vitro Classification of Lung Cancer Genetic Mutations m e m e R b r e si h t EGFR = Epidermal Growth Factor Receptor; KRAS = v-ki-ras2 Kirsten rat sarcoma viral oncogene homolog; ALK = Anaplastic Lymphoma receptor tyrosine Kinase

79 New Frontiers in Lung Cancer Conclusion Temper the Nihilism Support the development of new tools

80 New Frontiers in Lung Cancer Conclusion Temper the Nihilism Support the development and deployment of new tools

81 NEW FRONTIER: JOIN US!! Thank you for your time

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